课件：肿瘤侵袭和转移.ppt

整合素对肿瘤细胞的侵袭和迁移作用 直接介导黏附于细胞外基质，影响细胞外环境 作为细胞表面受体，将接收的信号传递到细胞核内，控制细胞骨架变形和能量代谢，改变细胞的形态、移行、增殖和寿命 诱导活化蛋白溶解酶，促进细胞外基质和基底膜的降解，进一步促进肿瘤转移 启动某些细胞逃逸机制，抑制细胞凋亡 三、纤维蛋白溶解酶及其调节因子 纤维蛋白溶解酶激活因子（PA) 组织型PA(t-PA) 尿激酶型PA(u-PA) 纤维蛋白溶解酶抑制因子（PAI） PAI-1 PAI-2 PAI-3 四、 MMP (matrix metalloproteinases) MMPs are a tight regulated family of proteolytic enzymes that degrade components of the extracellular matrix and basement membrane. MMPs play a role in a wide range of tumorigenesis, including early carcinogenesis events, tumor growth and tumor invasion and metastasis. The MMP family (at least 23 members) Classification Soluble (secreted)-type MMP Based on substrate specificity: collagenases, gelatinases, stromelysins, matrilysins, the others Most soluble-type MMPs are secreted from the cell as inactive zymogen with the prodomain Activation requires the disruption of the cysteine-zinc interaction possibly by tissue or plasma proteinases, and this process often consists of a two-steps reaction membrane-anchored MMPs Based on the membrane –anchoring mechanisms, these MT-MMPs can be further divided into: Type I transmembrane MMP: MT1-3 and MT5-MMP The glycosylphophatidylinositol(GPI)-anchored MMP: MT4-and MT-6-MMP typeII transmembrane MMP: MMP-23 or CA-MMP (2) structure (3) MMPs share the following common characteristics: (4) Function The soluble MMP may show broader accessibility into ECM and play a role in tissue remodeling events The MT-MMP are predominantly involved in regulation of pericellular environments closely associated with cellular functions, including migration and invasion 2. Involvement of MMP in tumor invasion and metastasis Cell surface localization and activation of MMP is essential for cells to migrate, through rearrangement of ECM to suit cell migration. MMP mainly involved in metastasis are different in some tumors MMP induction by cell-cell interaction and emmprin Emmprin(extracellular matrix metalloproteinase inducer) The cDNA for human emmprin encodes a 269 amino acid residu